CA2870188A1 - Polylactide and calcium phosphate compositions and methods of making the same - Google Patents
Polylactide and calcium phosphate compositions and methods of making the same Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/32—Phosphorus-containing compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/32—Phosphorus-containing compounds
- C08K2003/321—Phosphates
- C08K2003/325—Calcium, strontium or barium phosphate
Abstract
A method is provided for synthesizing polylactide/calcium phosphate composites. In one form, the calcium phosphate material is protonated with an acid and after protonation, combined with a silane material to form an intermediate silanized calcium phosphate material. The intermediate silanized calcium phosphate material is then combined with a lactide material to form the polylactide/ calcium phosphate matrix material that has at least 1.3 times the tensile strength of a polylactide/calcium phosphate material prepared without combining the silane with the calcium phosphate material.
Description
POLYLACTIDE AND CALCIUM PHOSPHATE, COMPOSITIONS
AND METHODS OF MAKING THE SAME
FIELD
[00011 This application claims the benefit of US, Provisional Application Serial No, 61/623,490, filed April 12, 2012, which is incorporated as if fully rewritten herein and U. S.
Provisional Application Serial No. 61/623,483, filed April 12, 2012 which also is incorporated herein as if fully rewritten, [0002] The present application is directed to compositions including calcium phosphate composites and methods for making the same. More particularly, the methods and resulting composites include polylactides and calcium phosphate materials such as tetracalcium phosphate.
BACKGROUND
AND METHODS OF MAKING THE SAME
FIELD
[00011 This application claims the benefit of US, Provisional Application Serial No, 61/623,490, filed April 12, 2012, which is incorporated as if fully rewritten herein and U. S.
Provisional Application Serial No. 61/623,483, filed April 12, 2012 which also is incorporated herein as if fully rewritten, [0002] The present application is directed to compositions including calcium phosphate composites and methods for making the same. More particularly, the methods and resulting composites include polylactides and calcium phosphate materials such as tetracalcium phosphate.
BACKGROUND
[0003] Bioresorable compositions such as polylactides (PLA) are useful for bone fixation and bone repair and have the advantage of not requiring surgical removal after the bone heals.
However, the use of polylactides for bone fixation and bone repair can lead to a variety of undesirable side effects, such as inflammation or allergic reactions.
[00041 Many calcium phosphates are excellent candidates for use as bone repair substitutes because of their excellent tissue response and osteooconductivity.
Incorporating calcium phosphate ceramics, e.g., hydroxyapatite (HA, Calo(PO4)6(01-1)2), tricalcium phosphate (TCP, Ca3(PO4)2) and tetracalcium phosphate (ITCP, Ca4(PO4)20), mon.ocalcium phosphate (MCP, Ca (H2PO4)2), &calcium phosphate (DCP, CatIP04), amorphous calcium phosphate (ACP.
Ca3(PO4)2)õ octacalcium phosphate (OCP, Ca8E12(PO4)6), carbonate-substituted apatite (CAP, Calo-x/2(PO4)6,(CO3)(OH)2), and fluoroapatite (FAP., Can(F04)6(OH.,92) into the polymer matrix has been proved to be an effective way to improve the clinical perform.an.ce, [00051 Combining bioactive calcium phosphates, such as hydroxyapatite (HA), 'icalcium phosphate (TCP), tetracalcium phosphate (TTCP), monocalcium phosphate (MCP), dicalcium.
phosphate (DCP), amorphous calcium phosphate (ACP), octacalcium phosphate (OCP), carbonate-substituted apatite (CAP), fluoroapatite (FAP) and other halogen-substitute apatite (XA.P) with PIA yields a composition similar to the composition found in bone and teeth, SUBSTITUTE SHEET (RULE 26) Polylactide/calcium phosphate composites make an implant more osteocondu.ctive and aides in lessening the side-effect of PLA by neutralizing acidic bio-degraded by-products of PLA.
Although HA and TCP can he used to consume acidity, they are not suitable for buffering at pH 7.4 due to the complex phenomenon of dissolution-reprecipitation of the solid phase.
Because of the slow dissolution, it generally takes a long time for the composite to degrade.
[0006] Polylactide/calcium phosphate composites have the potential of improving clinical bone healing. However, current polylactide/calcium phosphate composites have a significant setback due to its mechanical weakness. Due to the weak interfacial strength between inorganic particulate and PLA matrix, as a result, brittle fracture behavior is observed in this biocomposite system.
[0007] The current methods of synthesizing polylactide/calcium phosphate composites mostly consist of direct blending or mixing of the polylactide with calcium phosphate particles.
This creates weak interfacial adhesion between PLA (hydrophobic) and calcium phosphate (hydrophilic) moieties along with agglomeration or clumping of calcium phosphate particles.
SUMMARY
[0008] It has been unexpectedly found that polylactide/calcium phosphate material may be prepared whereby the calcium phosphate material having a general formula of Caa(P0()),Xõ
where p-1-10, q=1-40 and z-I-5 and where X may be OH, 0, CO3, F, CI, Br, in particular hydroxyapatite (HA), tricalcium phosphate (TCP), tetracalcium phosphate (ITCP), monocalcium phosphate (MCP), dicalcium phosphate (DCP), amorphous calcium phosphate (.A.CP), octacalcium phosphate (0CP), carbonate-substituted apatite (CAP), fluoroapatite (FAP) and other halogen-substitute apatite (XAP), is modified prior to coupling with the polylactide having a general formula of -(OCR1R2CO)n- or --(R3C00)11-, where Re R2, R3 can be any of H, alkyl less than CIO and other substitutes and n = 1-4. Other degradable polymer materials besides polylactide may also be used such as polyca.prola.ctone (PCL), polyglycolide (PGA) and PLGA (polylactide-co-glycolide), polyhydroxybutyrate, poly(hydroxyvalerate, poly(carbonates), polyphosphazene, pokyanhydrides, polycaprolactone, polyurethane or other polyesters and natural origin degradable polymers such as cellulose, starch, gelatin, chitosare peptides and their derivatives.
SUBSTITUTE SHEET (RULE 26) [0009] In one form, the calcium phosphate material is protonated with an acid, and after protonation, combined with a silane material having a general formula of (R10)(R20)(R30),Si-R4-Y, where Y can be OH, NH2, SF-I, Cl; R1, R2, R.3 can be the same or different from alkyl (C1-C10), R1 is alkyl (C1-C20), the RO on the silane reacting with the phosphate which is proton.ated to form an intermediate silanized calcium phosphate material! for example silanized tetra.calcium phosphate material. The intermediate silanized calcium phosphate material may then be combined with a lactide material having a general formula ofe(OCR1R2C0)õ- or a (R3C00)õ-, where R1, R2, R3 can be any of H, alkyl less than C10 and other substitutes and n = 1-4 to form the polylactide/calcium phosphate matrix material, the reaction between the intermediate and the silane initiated by Y on the silane. The polylactide/calcium phosphate matrix material has a tensile strength that is at least 1.3 times the tensile strength of a polylactide/calcium phosphate material prepared without combining the slime with the calcium phosphate material.
[0010] In particular, tetracalcium phosphate (TTCP) has relatively desirable bioactivity and is a soluble form of calcium phosphate. TTCP was also proved to be biocompatible and possessed osteoconductive properties. Because of the higher Ca/P ratio of TTCP
compared with HA, complete hydration is expected to form calcium hydroxide and a strong alkaline pH
value. The degradation alkaline functionality could compensate the release of acidic monomers from biodegradable PLA., thus improving tissue compatibility.
[0011] Combining the protonated calcium phosphate source with a silane material may further include pyromellitic dianhydride which may improve the storage modulus of the polylactide/calcium phosphate matrix material. It is believed that such polylactide/calcium phosphate composite prepared from an intermediate silanized calcium phosphate material may have increased tensile strength compared to a polylactide/calcium phosphate material that has not been modified with a silane material.
[0012] In one form, protonated calcium phosphate material is combined with a silane material to form an intermediate silanized calcium phosphate material. The intermediate silanized calcium phosphate material may then be combined with FLA. Further, an acid anhydride material, such as pyromellitic dianhydride may be combined to the intermediate silanized calcium phosphate material along with the PLA and/or after addition of the PLA.
SUBSTITUTE SHEET (RULE 26) Additionally, other biocompatible acid anhydrides may also be used, such as diacid anhydrides and triacid. anhydrides.
[00131 According to one form, the protonated calcium phosphate source is modified with the slime coupling containing material to increase the dispersion of calcium phosphate in an intermediate silanized calcium phosphate material or matrix. In one form, the intermediate silanized calcium phosphate material results in P-O-Si structures, where a plurality of the -OH
groups of calcium phosphate have been reacted and the silane coupling containing material and covers the calcium phosphate surface, this increases the stability of a tetracalcium matrix in suspension.
[00141 The method may also include the step of combining calcium phosphate material with a silane material which further includes combining pyromellitic dianhydride (PMDA) with the silanized calcium phosphate material.
[00151 In one form, the silane coupling material includes N-(2-aminoethyl)-aminoproplytrimethoxysilane (ARAI'S). According to one form, the silane coupling material can include any other silane agent with a general formula of (Ri0)(R20)(R,30)Si-R4-Y, where Y
can be OH, NT-T2õ SH, CI; Re R2, R3 can be the same or different CI-C1.0 al.kyl, R4 is CI-C20 alkyl.
In this regard, in one form, the calcium phosphate source, preferably tetracalcium phosphate is suspended in a phosphoric acid within alcohol, acetone, ether, preferable an ethanol phosphoric acid, [00161 The polylactide/calcium phosphate produced by combining the calcium phosphate source with the silane coupling containing material creates a PO-Si structure on the surface of the intermediate silanized calcium phosphate material.
[00171 In one form, the method of synthesis may provide increased tensile strength when compared to that of polylactide alone, [00181 By one approach, the composition comprises significantly higher amount of polylactide covalently attached to calcium phosphate than that of current compositions produced by conventional methods.
SUBSTITUTE SHEET (RULE 26) BRJEF DESCRIPTION OF THE FIGURES
[0019] Figure 1 illustrates X thermogravimetric analysis (TGA) curves of various tetra.calcillin phosphate composites.
[0020] Figure 2 illustrates FTIR spectrometry of tetracalciu.m phosphate and intermediate silanized tetracalcium phosphate.
[0021] Figure 3 illustrates photographs of tetracalcium phosphate and intermediate silanized tetra.calcium phosphate dispersed in dichloromethane.
[0022] Figure 4 illustrates tensile properties of various forms of polylactide/tetracalcium phosphate composites.
[0023] Figure 5 illustrates bending properties of various forms of polylactide/tetracalcium phosphate composites.
[0024] Figures 6A and 6B illustrate dynamic mechanical property curves of various forms of polylactide/tetracalcium phosphate composites.
[0025] Figures 7A and 7B illustrate scanning electron microscope images of various forms of polylactide/calci LEM phosphate composites.
DETAILED DESCRIPTION
[0026] Described herein are methods and compositions comprising polylactide/calcium phosphate composites. In one form, the general method provides synthesis of polylactide/calcium phosphate by combining a protonated calcium phosphate material having a general formula of Cap(1304),4X, where p-140, q-1-40 and zo.1-5, where X may be OH, 0, CO3, F, Cl, Brwith a silane material having a general formula of (R10)(R20)(R30)Si-R4--Y, where Y can be OH, NH2, SH, CI; Ri, R2, R3 can be the same or different Cl-C10 alkyl, R4 is C1.-C20 alkyl to yield an intermediate grafted silanized calcium phosphate material that improves dispersion of calcium phosphate in a matrix. It should be noted that when referring to a composite material, the material includes lactide/modified calcium phosphate material along with additional lactide material. In other words, the lactide/modified calcium phosphate material is in a matrix with the additional lactide material.
SUBSTITUTE SHEET (RULE 26) [0027] In one aspect, combining the protortated calcium phosphate source with a silane coupling containing material may further include combining pyromellitic dianhydride which may improve the storage modulus of the polylactide/calcium phosphate matrix material. It is believed that such a composite polylactide/calcium phosphate prepared from an intermediate grafted silanized calcium phosphate matrix material may have increased tensile strength compared to a polylactideicalcium phosphate material that has not been modified with a silane coupling containing material.
[0028] The calcium phosphate material may include a variety of materials such as Cap(1.304).4X, where p----140, q=1-10 and z=1-5 and where X may be OH, 0, CO3.
F, Cl, Br including proton.ated phosphate (e.g., HP042-, H2PO4), in particular hydroxyapatite (HA), tricalcium phosphate (TCP)õ tetracalcium phosphate (TTCP), monocalcium phosphate (MCP), dicalcium phosphate (DCP), amorphous calcium phosphate (ACP), octacalcium phosphate (0CP), carbonate-substitue apatite (CAP), fluoroapafite (FAP) and other halogen-substitute apatite (XAP), preferable proton.ated .tetracalcium phosphate. The protonated calcium phosphate is prepared by treatment with an acid, exemplary acids include phosphoric acid, phosphonic acid, sulfonic acid, carboxylic acid, preferable diluted phosphoric acid. In one form, a range of the molar ratio of acid phosphate in calcium phosphates can be 1:10 or less, preferably around 1:50.
[0029] The silane material may include materials having the general formula (R10)(R20)(R30),Si-R4-Y, where Y can be OH, NH2, SH, CI; F(1, R2, R3 can be the same or different from alkyl (Ci-C10), R4 is alkyl (C1-C20), such as N-(2-aminoethyl)-aminoproplytrimethoxysilane (AEPS). The range of silane can be 1:2 or less, preferably around 1:20 in relation to calcium phosphate.
[0030] The lactide material may include materials having the general formula -(OCR1R2C0)1,- or -(R3C00),-, where R1, R2, 1R3 can be any of H, alkyl less than C1.0 and other substitutes. Further degradable polymer materials that may be used include polycaprolactone (PCL), polyglycolide (PGA) and PLGA (polylactide-co-glycolide), polyhydroxybutyrate, poly(hydroxyvalerate, poly(carbonates), polyphosphazene, polyanhydrides, polyurethane or other polyesters and natural origin degradable polymers such as cellulose, starch, gelatin, chitosan, peptides and their derivatives. The amount of the lactide material may range from 1%
However, the use of polylactides for bone fixation and bone repair can lead to a variety of undesirable side effects, such as inflammation or allergic reactions.
[00041 Many calcium phosphates are excellent candidates for use as bone repair substitutes because of their excellent tissue response and osteooconductivity.
Incorporating calcium phosphate ceramics, e.g., hydroxyapatite (HA, Calo(PO4)6(01-1)2), tricalcium phosphate (TCP, Ca3(PO4)2) and tetracalcium phosphate (ITCP, Ca4(PO4)20), mon.ocalcium phosphate (MCP, Ca (H2PO4)2), &calcium phosphate (DCP, CatIP04), amorphous calcium phosphate (ACP.
Ca3(PO4)2)õ octacalcium phosphate (OCP, Ca8E12(PO4)6), carbonate-substituted apatite (CAP, Calo-x/2(PO4)6,(CO3)(OH)2), and fluoroapatite (FAP., Can(F04)6(OH.,92) into the polymer matrix has been proved to be an effective way to improve the clinical perform.an.ce, [00051 Combining bioactive calcium phosphates, such as hydroxyapatite (HA), 'icalcium phosphate (TCP), tetracalcium phosphate (TTCP), monocalcium phosphate (MCP), dicalcium.
phosphate (DCP), amorphous calcium phosphate (ACP), octacalcium phosphate (OCP), carbonate-substituted apatite (CAP), fluoroapatite (FAP) and other halogen-substitute apatite (XA.P) with PIA yields a composition similar to the composition found in bone and teeth, SUBSTITUTE SHEET (RULE 26) Polylactide/calcium phosphate composites make an implant more osteocondu.ctive and aides in lessening the side-effect of PLA by neutralizing acidic bio-degraded by-products of PLA.
Although HA and TCP can he used to consume acidity, they are not suitable for buffering at pH 7.4 due to the complex phenomenon of dissolution-reprecipitation of the solid phase.
Because of the slow dissolution, it generally takes a long time for the composite to degrade.
[0006] Polylactide/calcium phosphate composites have the potential of improving clinical bone healing. However, current polylactide/calcium phosphate composites have a significant setback due to its mechanical weakness. Due to the weak interfacial strength between inorganic particulate and PLA matrix, as a result, brittle fracture behavior is observed in this biocomposite system.
[0007] The current methods of synthesizing polylactide/calcium phosphate composites mostly consist of direct blending or mixing of the polylactide with calcium phosphate particles.
This creates weak interfacial adhesion between PLA (hydrophobic) and calcium phosphate (hydrophilic) moieties along with agglomeration or clumping of calcium phosphate particles.
SUMMARY
[0008] It has been unexpectedly found that polylactide/calcium phosphate material may be prepared whereby the calcium phosphate material having a general formula of Caa(P0()),Xõ
where p-1-10, q=1-40 and z-I-5 and where X may be OH, 0, CO3, F, CI, Br, in particular hydroxyapatite (HA), tricalcium phosphate (TCP), tetracalcium phosphate (ITCP), monocalcium phosphate (MCP), dicalcium phosphate (DCP), amorphous calcium phosphate (.A.CP), octacalcium phosphate (0CP), carbonate-substituted apatite (CAP), fluoroapatite (FAP) and other halogen-substitute apatite (XAP), is modified prior to coupling with the polylactide having a general formula of -(OCR1R2CO)n- or --(R3C00)11-, where Re R2, R3 can be any of H, alkyl less than CIO and other substitutes and n = 1-4. Other degradable polymer materials besides polylactide may also be used such as polyca.prola.ctone (PCL), polyglycolide (PGA) and PLGA (polylactide-co-glycolide), polyhydroxybutyrate, poly(hydroxyvalerate, poly(carbonates), polyphosphazene, pokyanhydrides, polycaprolactone, polyurethane or other polyesters and natural origin degradable polymers such as cellulose, starch, gelatin, chitosare peptides and their derivatives.
SUBSTITUTE SHEET (RULE 26) [0009] In one form, the calcium phosphate material is protonated with an acid, and after protonation, combined with a silane material having a general formula of (R10)(R20)(R30),Si-R4-Y, where Y can be OH, NH2, SF-I, Cl; R1, R2, R.3 can be the same or different from alkyl (C1-C10), R1 is alkyl (C1-C20), the RO on the silane reacting with the phosphate which is proton.ated to form an intermediate silanized calcium phosphate material! for example silanized tetra.calcium phosphate material. The intermediate silanized calcium phosphate material may then be combined with a lactide material having a general formula ofe(OCR1R2C0)õ- or a (R3C00)õ-, where R1, R2, R3 can be any of H, alkyl less than C10 and other substitutes and n = 1-4 to form the polylactide/calcium phosphate matrix material, the reaction between the intermediate and the silane initiated by Y on the silane. The polylactide/calcium phosphate matrix material has a tensile strength that is at least 1.3 times the tensile strength of a polylactide/calcium phosphate material prepared without combining the slime with the calcium phosphate material.
[0010] In particular, tetracalcium phosphate (TTCP) has relatively desirable bioactivity and is a soluble form of calcium phosphate. TTCP was also proved to be biocompatible and possessed osteoconductive properties. Because of the higher Ca/P ratio of TTCP
compared with HA, complete hydration is expected to form calcium hydroxide and a strong alkaline pH
value. The degradation alkaline functionality could compensate the release of acidic monomers from biodegradable PLA., thus improving tissue compatibility.
[0011] Combining the protonated calcium phosphate source with a silane material may further include pyromellitic dianhydride which may improve the storage modulus of the polylactide/calcium phosphate matrix material. It is believed that such polylactide/calcium phosphate composite prepared from an intermediate silanized calcium phosphate material may have increased tensile strength compared to a polylactide/calcium phosphate material that has not been modified with a silane material.
[0012] In one form, protonated calcium phosphate material is combined with a silane material to form an intermediate silanized calcium phosphate material. The intermediate silanized calcium phosphate material may then be combined with FLA. Further, an acid anhydride material, such as pyromellitic dianhydride may be combined to the intermediate silanized calcium phosphate material along with the PLA and/or after addition of the PLA.
SUBSTITUTE SHEET (RULE 26) Additionally, other biocompatible acid anhydrides may also be used, such as diacid anhydrides and triacid. anhydrides.
[00131 According to one form, the protonated calcium phosphate source is modified with the slime coupling containing material to increase the dispersion of calcium phosphate in an intermediate silanized calcium phosphate material or matrix. In one form, the intermediate silanized calcium phosphate material results in P-O-Si structures, where a plurality of the -OH
groups of calcium phosphate have been reacted and the silane coupling containing material and covers the calcium phosphate surface, this increases the stability of a tetracalcium matrix in suspension.
[00141 The method may also include the step of combining calcium phosphate material with a silane material which further includes combining pyromellitic dianhydride (PMDA) with the silanized calcium phosphate material.
[00151 In one form, the silane coupling material includes N-(2-aminoethyl)-aminoproplytrimethoxysilane (ARAI'S). According to one form, the silane coupling material can include any other silane agent with a general formula of (Ri0)(R20)(R,30)Si-R4-Y, where Y
can be OH, NT-T2õ SH, CI; Re R2, R3 can be the same or different CI-C1.0 al.kyl, R4 is CI-C20 alkyl.
In this regard, in one form, the calcium phosphate source, preferably tetracalcium phosphate is suspended in a phosphoric acid within alcohol, acetone, ether, preferable an ethanol phosphoric acid, [00161 The polylactide/calcium phosphate produced by combining the calcium phosphate source with the silane coupling containing material creates a PO-Si structure on the surface of the intermediate silanized calcium phosphate material.
[00171 In one form, the method of synthesis may provide increased tensile strength when compared to that of polylactide alone, [00181 By one approach, the composition comprises significantly higher amount of polylactide covalently attached to calcium phosphate than that of current compositions produced by conventional methods.
SUBSTITUTE SHEET (RULE 26) BRJEF DESCRIPTION OF THE FIGURES
[0019] Figure 1 illustrates X thermogravimetric analysis (TGA) curves of various tetra.calcillin phosphate composites.
[0020] Figure 2 illustrates FTIR spectrometry of tetracalciu.m phosphate and intermediate silanized tetracalcium phosphate.
[0021] Figure 3 illustrates photographs of tetracalcium phosphate and intermediate silanized tetra.calcium phosphate dispersed in dichloromethane.
[0022] Figure 4 illustrates tensile properties of various forms of polylactide/tetracalcium phosphate composites.
[0023] Figure 5 illustrates bending properties of various forms of polylactide/tetracalcium phosphate composites.
[0024] Figures 6A and 6B illustrate dynamic mechanical property curves of various forms of polylactide/tetracalcium phosphate composites.
[0025] Figures 7A and 7B illustrate scanning electron microscope images of various forms of polylactide/calci LEM phosphate composites.
DETAILED DESCRIPTION
[0026] Described herein are methods and compositions comprising polylactide/calcium phosphate composites. In one form, the general method provides synthesis of polylactide/calcium phosphate by combining a protonated calcium phosphate material having a general formula of Cap(1304),4X, where p-140, q-1-40 and zo.1-5, where X may be OH, 0, CO3, F, Cl, Brwith a silane material having a general formula of (R10)(R20)(R30)Si-R4--Y, where Y can be OH, NH2, SH, CI; Ri, R2, R3 can be the same or different Cl-C10 alkyl, R4 is C1.-C20 alkyl to yield an intermediate grafted silanized calcium phosphate material that improves dispersion of calcium phosphate in a matrix. It should be noted that when referring to a composite material, the material includes lactide/modified calcium phosphate material along with additional lactide material. In other words, the lactide/modified calcium phosphate material is in a matrix with the additional lactide material.
SUBSTITUTE SHEET (RULE 26) [0027] In one aspect, combining the protortated calcium phosphate source with a silane coupling containing material may further include combining pyromellitic dianhydride which may improve the storage modulus of the polylactide/calcium phosphate matrix material. It is believed that such a composite polylactide/calcium phosphate prepared from an intermediate grafted silanized calcium phosphate matrix material may have increased tensile strength compared to a polylactideicalcium phosphate material that has not been modified with a silane coupling containing material.
[0028] The calcium phosphate material may include a variety of materials such as Cap(1.304).4X, where p----140, q=1-10 and z=1-5 and where X may be OH, 0, CO3.
F, Cl, Br including proton.ated phosphate (e.g., HP042-, H2PO4), in particular hydroxyapatite (HA), tricalcium phosphate (TCP)õ tetracalcium phosphate (TTCP), monocalcium phosphate (MCP), dicalcium phosphate (DCP), amorphous calcium phosphate (ACP), octacalcium phosphate (0CP), carbonate-substitue apatite (CAP), fluoroapafite (FAP) and other halogen-substitute apatite (XAP), preferable proton.ated .tetracalcium phosphate. The protonated calcium phosphate is prepared by treatment with an acid, exemplary acids include phosphoric acid, phosphonic acid, sulfonic acid, carboxylic acid, preferable diluted phosphoric acid. In one form, a range of the molar ratio of acid phosphate in calcium phosphates can be 1:10 or less, preferably around 1:50.
[0029] The silane material may include materials having the general formula (R10)(R20)(R30),Si-R4-Y, where Y can be OH, NH2, SH, CI; F(1, R2, R3 can be the same or different from alkyl (Ci-C10), R4 is alkyl (C1-C20), such as N-(2-aminoethyl)-aminoproplytrimethoxysilane (AEPS). The range of silane can be 1:2 or less, preferably around 1:20 in relation to calcium phosphate.
[0030] The lactide material may include materials having the general formula -(OCR1R2C0)1,- or -(R3C00),-, where R1, R2, 1R3 can be any of H, alkyl less than C1.0 and other substitutes. Further degradable polymer materials that may be used include polycaprolactone (PCL), polyglycolide (PGA) and PLGA (polylactide-co-glycolide), polyhydroxybutyrate, poly(hydroxyvalerate, poly(carbonates), polyphosphazene, polyanhydrides, polyurethane or other polyesters and natural origin degradable polymers such as cellulose, starch, gelatin, chitosan, peptides and their derivatives. The amount of the lactide material may range from 1%
SUBSTITUTE SHEET (RULE 26) to about 99% of the overall composite composition. in one form, the amount of lactide is about 50% of the overall composite composition, [0031] In one embodiment, grafting by silanization at the surface of the calcium phosphate is prepared by mixing the protonated calcium phosphate and a silane material (total 50 g with a weight ratio of silane and calcium phosphate 1;10), exemplary coupling materials are OR10)(R20)(R30)Si.-R4-Y, where Y can be OH, NH2, SH, CI; R1, R2, R3 can be the same or different from alkyl (0.-C1.0), R4 is alkyl (C1.-C20), preferably AEAPS, in an anhydrous solvent, such as toluene, acetone, ether (200 mt), preferably toluene mixed with a gas used to displace oxygen-and moisture-containing air, an exemplary gas is nitrogen or argon. The silanized calcium phosphate was filtered and repeatedly washed with an anhydrous alcohol, acetone, ether, exemplary anhydrous solutions include alcohols, preferably ethanol (50 mL
three times), for the complete removal of non-bound coupling agent. The silanized calcium phosphate was dried in an oven for 8 72 hours, preferably 24 hours at 50450 'C.', preferably 110 C.
[0032] In one aspect, polylactide/calcium phosphate was prepared by melt compound at 200-250 C., preferably 230 C for FLA with a screw speed of 10-100 rpm, preferably 50 rpm.
Silanized calcium phosphate was mixed with polylactide or an.alougs, e.g., PGA, PI,GA, PC1, in a weight ratio to calcium phosphate 1% - 99%, preferably 50%, for 1-30 minutes. Additionally, PMDA was further added and mixed in 0%-5% wt, preferably 0.2%. The samples were injection molded in an injection-molding machine, such as Polylab OS RheoDrive 7 (Germany). The injection and holding time were set as 15 seconds and 30 seconds, with a mold temperature of 50420 C, preferably 85 'C.
[0033] Exemplary methods for making the composite will be described below.
[0034] Surface protonation of tetracalciutm phosphate (TTCP) [0035] Tetracalcium phosphate was stirred with dilute anhydrous alcohol phosphoric acid (50:1 w/ w) at room temperature for about 1 hour and then subsequently washed with anhydrous ethanol. The protonated TTCP particles were dried in the oven overnight at about 100 C. Other acid to activate calcium phosphate can be carbosxylic acid, sulfonic acid, phosphonic acid and sulfuric acid, hydrochloric acid, acetic acid, and any other acid.
three times), for the complete removal of non-bound coupling agent. The silanized calcium phosphate was dried in an oven for 8 72 hours, preferably 24 hours at 50450 'C.', preferably 110 C.
[0032] In one aspect, polylactide/calcium phosphate was prepared by melt compound at 200-250 C., preferably 230 C for FLA with a screw speed of 10-100 rpm, preferably 50 rpm.
Silanized calcium phosphate was mixed with polylactide or an.alougs, e.g., PGA, PI,GA, PC1, in a weight ratio to calcium phosphate 1% - 99%, preferably 50%, for 1-30 minutes. Additionally, PMDA was further added and mixed in 0%-5% wt, preferably 0.2%. The samples were injection molded in an injection-molding machine, such as Polylab OS RheoDrive 7 (Germany). The injection and holding time were set as 15 seconds and 30 seconds, with a mold temperature of 50420 C, preferably 85 'C.
[0033] Exemplary methods for making the composite will be described below.
[0034] Surface protonation of tetracalciutm phosphate (TTCP) [0035] Tetracalcium phosphate was stirred with dilute anhydrous alcohol phosphoric acid (50:1 w/ w) at room temperature for about 1 hour and then subsequently washed with anhydrous ethanol. The protonated TTCP particles were dried in the oven overnight at about 100 C. Other acid to activate calcium phosphate can be carbosxylic acid, sulfonic acid, phosphonic acid and sulfuric acid, hydrochloric acid, acetic acid, and any other acid.
SUBSTITUTE SHEET (RULE 26) [0036] Grafting of N-(2-aminoethvi)-3-an-tinoproplytrimethowsilane LAEAPS) on the surface of TTCP
[0037] The silanization reaction was performed under reflux using a suspension of protonated tetracakium phosphate and N-(2-aminoethyl)-3.-aminoproplytrimethoxysilane in about 2:1 ratio in anhydrous toluene with continuous stirring under argon atmosphere at about 110 C for about 24 hours. The silanized tetracalcium phosphate (TTCP-AEAPS) was filtered and washed with anhydrous ethanol for complete removing of non-bounded coupling agent.
TTCP-AEAPS powders were dried in the oven overnight at about 100 C.
[0038] Preparation of PLAIPTCP composites [0039] The FLA/17C1 composites were prepared by melt compounding using a Haake Polylab OS RheoDrive 7 (Germany) at about 230 C. with a screw speed of about 50 rpm. Prior to melt processing. TTCP and TTCP-AEAPS were dried in a vacuum oven overnight at about 100 C. The ingredients of desired proportions of PLA and TTCP were incorporated into the mixer for about 3 minutes, then desired PMDA (0.2 wt%) was put into the mixer for about another 4 minutes. The samples were injection molded into standard samples in an injection molding machine (liaake Minijet IT, Thermo Fisher Scientific, Co. Ltd, Germany) at about 230 C. The injection and holding time were set at about 15 s and 30 s, respectively. The injection pressure and holding pressure were 85 MPa and 15 MPa, with the mold temperature of about 85 C.
[0040] In one aspect. FTIR spectrometry was performed with KBr pellets using a Thermo Nicolet 6700 FTIR spectrum analyzer in the wavenumber range of 4000 to 650 cirri. Spectra were signal averaged over 16 scans at a resolution of 4 cm-', The amount of surface grafted compound was characterized by TGA (Perkin-Elmer, Pyris 1) in nitrogen atmosphere from about 100 C. to about 750 C at a heating rate of about 20 C/min with airflow of about 80 ML/min. The amount of slime on the surface of TTCP was supposed to be the weight loss percentage. An SEM (ISM-6700F field emission Scanning Electron Microscope) was used to investigate the morphology of the fracture surface. Prior to the SEM
examination, samples were submerged in liquid nitrogen for about 30 minutes and broken to expose the internal structure for SEM studies. The tensile property was characterized at room temperature according to ISO 527 on an Instron 3365 universal test machine (Instron Corporation, USA).
The cross-head SUBSTITUTE SHEET (RULE 26) speed of the apparatus was 5 mm/mm. The bending property was measured at room temperature according to ISO 178 on an. Instron 3365 machine at a bending speed of about 1 mm,/ min. The mechanical data were obtained by averaging of three specimens.
Dynamic mechanical analysis (DMA Q800, TA Instruments) was performed with a single-cantilever clamp on sample bar measuring 35 x4x2 mm.3. A. temperature ramp experiment was conducted with amplitude of 15 pm from -50 C to 150 C. at a heating rate of 3 C/min with. a constant frequency of 1 Hz.
[0041] EXAMPLES
[0042] Example 1 [0043] Grafting of AEAPS on the surface of TTCP
[0044] AEAPS can directly react with hydroxyl through -OR group of the silane derivatives. Amino groups of the silane derivatives may further react towards the terminal carboxylic groups. PMDA is believed to react with amino group of the AEAPS and terminal hydroxyl groups of PLA. As a basis for the silanization at the surface of TTCP, protanation of the TTCP surface was necessary. The treatment of TTCP with diluted phosphoric acid led to the formation of calcium hydrogen phosphate at the surface of TTCP. As shown in Figurel, there is almost no weight loss for non-protonated TTCP and non-protonated TTCP-AEAPS
even at 750 C. It is believed that AEAPS could hardly be grafted onto the surface of TTCP before the surface protonation procedure. After surface protonationõ AEAPS was immobilized on the surface of Trcp. The protonated TTCP showed high thermal stability and displayed about 0.4% weight loss even at 750 C. For TTCP-AEAPS, it had appreciable weight loss, which was attributed to the decomposition of the grafted AEAPS. There was almost 5 wt%
AEAPS
immobilized on the surface of TTCP.
[0045] FTIR was used to indicate that .AEAPS is grafted on the surface of Trcp after silanization (Figure 2). The broad strong bands around .3700-3200 cm-1 are assigned to the hydroxyl stretching vibration of TTCP. The bond in 1700-730 cm-1 region corresponds to the characteristic peak of TTCP. After the silanization, new characteristic peaks were observed.
The band around 1735-1550 cm4 is ascribed to hydroxyl bending after the pro tonation of the TTCP surface, The characteristic of CH2 bending appears around 1490-1380 cm4.
The SUBSTITUTE SHEET (RULE 26) shoulder peak around 1570 cm-1 attributed to NH bending is not observed because of the low content of AEAPS on TTCP surface and overlapping of broad strong hydrogen band around 1650 cm-1. It is also noticed that a special peak at 964 cm-1 exists neither in TTCP nor in AEAPS
spectrum, [00461 The structure P-O-Si resulting from the coupling reaction between the A.EAPS and TTCP may contribute to this newly emerged peak at 964 cm4, The covalent bond was generated between TTCP and AEAPS. 0.5 g TTCP and TTCP-AEAR5 were dispersed into 4 itiL
dichloromethane, respectively. The suspensions were magnetic stirred vigorously for minutes. After that TTCP deposited to the bottom immediately, while the TTCP-AEAPS
solution was even stable after 20 minutes (Fig. 3), Neat TTCP tends to form large agglomerates.
After silanization, most of hydroxyl groups of TTCP have been reacted and AEAPS was covered the TTCP surface, which could increase the stability of the suspension.
[00471 Example 2 [0048] Mechanical property [00491 It is believed that due to the presence of AEAPS on the surface; the interfacial strength was improved. The mechanical strength of PLA/TTCP-AEAPS composites was higher than that of PLA./ TTCP composites with different contents (Figure 4). For example, the tensile strength was 68.4 MPa for PLA/TTCP-AEAPS composite (20 wt% - meaning the overall composite material includes 20wt% modified TTCP-AEAPS). However, it dropped to 515 MPa, when 20 wt% TTCP was incorporated into the matrix. The improved coupling leads to areas with ductile stretched polymer at the interface between PIA and TTCP. The surface modification may contribute to improving the interfacial adhesion. It is well known that there is big agglomeration when inorganic fillers are incorporated into polymeric materials especially at a high loading. Therefore, loosened clusters of TTCP could lead to breakdown of the composite.
[00501 The strength dropped linearly for PLA/TTCP composites. Better interfacial adhesion between filler and polymer matrix may help improve load transfer. The tensile strength was 68.4 MPa even with 20 wt% (meaning the overall composite material includes 20wt% modified TTCP.-.AEAPS) TTCP-AEAPS incorporation, which was 32% increase than that SUBSTITUTE SHEET (RULE 26) of PLA/TTCP composite (20 wt% - meaning the overall composite material includes 20wt?4, non-modified TTCP). In order to fulfill the various requirements, high loading of calcium phosphate cements are required.
[0051] The difference of tensile strength among the composites became smaller at high loading with and without PMDA incorporation. As shown in Figure 3, the tensile modulus increased for all the composites. After incorporating TTCP-AEAPS into the matrix (20 wt% -meaning the overall composite material includes 20wt% modified TTCP-AEAPS), the tensile modulus increased to 2000 MPa from 1550 MPa of pure PLA. It was believed that the functional particle could make contribution to improving the modulus, which might be attributed to good interfacial property. However, no remarkable difference was observed when PMDA
(0.2 wt% -meaning the overall composite material included 0.2wt% PN/TDA) was incorporated into the matrix, It might because there was limited reaction between anhydride and amino group occurred during the compounding process.
[0052] Regarding bending of the materials, TTCP may also contribute to improving the modulus but decreasing the strength (Figure 5), Because of the large agglomeration at high loading, the bending strength dropped even for the PLA/TTCP-AEAPS composites.
The particle would debond easily to enable crack initiation and propagation, Increasing TTCP
fraction increases the agglomeration, and more cracks can form and develop, thus decreasing the strength of the composites. There was no obvious difference among the composites, suggesting that interfacial strength between the particles and matrix was not strong enough, it has been reported that the surface modification method could improve the interfacial adhesion, but these interactions were weak during the bending study. Though the strength of the composites was a little lower compared to that of pure PIA/ the composite could be used in clinic.
[0053] Example 3 [0054] Dynamic mechanical property of PLA/TTCP composites [0055] Figure 6 shows the dynamic storage modulus of PLA and PLA/TTCP
composites (5 wt%) over a temperature range of -50 to 150 C1 It was found that the storage modulus increased with incorporation of filler over the entire temperature range. At -50 'V, the storage SUBSTITUTE SHEET (RULE 26) modulus for PIA was 3.21x109 Pa, which decreased with the increasing temperature; at the glass-transition temperature (Tg = 58.9 C) it dropped significantly. This is attributed to insufficient thermal energy to overcome the potential barrier for transitional and rotational motions of segments of the polymer molecules in the glassy region. Whereas above Tgõ the thermal energy becomes comparable to the potential energy barriers to the segmental motions.
[0056] For PLA/TTCP composite (5 wt% - meaning the overall composite material includes 20wt% modified TTCP-AEAFS), notable enhancement of the storage modulus (32%
increase) was observed in the lower temperature range, indicating that TTCP
had remarkable influence on the elastic properties of the PLA matrix. By incorporating ITCP-AEAPS (5 wt%) into the matrix, the storage modulus was 4.62x109 Pa, which is 44 % higher than that of neat PLA, it is believed that AEAPS was beneficial for the compatibility with the polar polymer matrix (Figure 7A). When 0.2 wt% PMDA (meaning the overall composite material included 0.2wt.% PMDA) was incorporated into the composites, the storage modulus was increased to 4.88x109 Pa (51% increase). The anhydride could react with the amino group which was grafted on the surface of TTCP, thus leading to a better interfacial property (Figure 7B). The anhydride might react with the terminal hydroxyl group of PLA, the interfacial property was improved. These two factors made contribution to the additional increase of the storage modulus. However, the degree of reaction between amino group and anhydride might be low and the increase was not very large. Tg increased from 63.2 C for PLA/TTCP-AEAPS (5% -meaning the overall composite material includes 5wt% modified TTCP-AEAPS) to 65.5 C when PMDA was incorporated into the composite (Figure 6B), signifying that a better interface was generated.
[0057] The foregoing descriptions are not intended to represent the only forms of the compositions and methods according to the present application. The percentages provided herein are by weight unless stated otherwise. Changes in form and in proportion of components, as well as the substitution of equivalents, are contemplated as circumstances may suggest or render expedient. Similarly, while compositions and methods have been described herein in conjunction with specific embodiments, many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description, SUBSTITUTE SHEET (RULE 26)
[0037] The silanization reaction was performed under reflux using a suspension of protonated tetracakium phosphate and N-(2-aminoethyl)-3.-aminoproplytrimethoxysilane in about 2:1 ratio in anhydrous toluene with continuous stirring under argon atmosphere at about 110 C for about 24 hours. The silanized tetracalcium phosphate (TTCP-AEAPS) was filtered and washed with anhydrous ethanol for complete removing of non-bounded coupling agent.
TTCP-AEAPS powders were dried in the oven overnight at about 100 C.
[0038] Preparation of PLAIPTCP composites [0039] The FLA/17C1 composites were prepared by melt compounding using a Haake Polylab OS RheoDrive 7 (Germany) at about 230 C. with a screw speed of about 50 rpm. Prior to melt processing. TTCP and TTCP-AEAPS were dried in a vacuum oven overnight at about 100 C. The ingredients of desired proportions of PLA and TTCP were incorporated into the mixer for about 3 minutes, then desired PMDA (0.2 wt%) was put into the mixer for about another 4 minutes. The samples were injection molded into standard samples in an injection molding machine (liaake Minijet IT, Thermo Fisher Scientific, Co. Ltd, Germany) at about 230 C. The injection and holding time were set at about 15 s and 30 s, respectively. The injection pressure and holding pressure were 85 MPa and 15 MPa, with the mold temperature of about 85 C.
[0040] In one aspect. FTIR spectrometry was performed with KBr pellets using a Thermo Nicolet 6700 FTIR spectrum analyzer in the wavenumber range of 4000 to 650 cirri. Spectra were signal averaged over 16 scans at a resolution of 4 cm-', The amount of surface grafted compound was characterized by TGA (Perkin-Elmer, Pyris 1) in nitrogen atmosphere from about 100 C. to about 750 C at a heating rate of about 20 C/min with airflow of about 80 ML/min. The amount of slime on the surface of TTCP was supposed to be the weight loss percentage. An SEM (ISM-6700F field emission Scanning Electron Microscope) was used to investigate the morphology of the fracture surface. Prior to the SEM
examination, samples were submerged in liquid nitrogen for about 30 minutes and broken to expose the internal structure for SEM studies. The tensile property was characterized at room temperature according to ISO 527 on an Instron 3365 universal test machine (Instron Corporation, USA).
The cross-head SUBSTITUTE SHEET (RULE 26) speed of the apparatus was 5 mm/mm. The bending property was measured at room temperature according to ISO 178 on an. Instron 3365 machine at a bending speed of about 1 mm,/ min. The mechanical data were obtained by averaging of three specimens.
Dynamic mechanical analysis (DMA Q800, TA Instruments) was performed with a single-cantilever clamp on sample bar measuring 35 x4x2 mm.3. A. temperature ramp experiment was conducted with amplitude of 15 pm from -50 C to 150 C. at a heating rate of 3 C/min with. a constant frequency of 1 Hz.
[0041] EXAMPLES
[0042] Example 1 [0043] Grafting of AEAPS on the surface of TTCP
[0044] AEAPS can directly react with hydroxyl through -OR group of the silane derivatives. Amino groups of the silane derivatives may further react towards the terminal carboxylic groups. PMDA is believed to react with amino group of the AEAPS and terminal hydroxyl groups of PLA. As a basis for the silanization at the surface of TTCP, protanation of the TTCP surface was necessary. The treatment of TTCP with diluted phosphoric acid led to the formation of calcium hydrogen phosphate at the surface of TTCP. As shown in Figurel, there is almost no weight loss for non-protonated TTCP and non-protonated TTCP-AEAPS
even at 750 C. It is believed that AEAPS could hardly be grafted onto the surface of TTCP before the surface protonation procedure. After surface protonationõ AEAPS was immobilized on the surface of Trcp. The protonated TTCP showed high thermal stability and displayed about 0.4% weight loss even at 750 C. For TTCP-AEAPS, it had appreciable weight loss, which was attributed to the decomposition of the grafted AEAPS. There was almost 5 wt%
AEAPS
immobilized on the surface of TTCP.
[0045] FTIR was used to indicate that .AEAPS is grafted on the surface of Trcp after silanization (Figure 2). The broad strong bands around .3700-3200 cm-1 are assigned to the hydroxyl stretching vibration of TTCP. The bond in 1700-730 cm-1 region corresponds to the characteristic peak of TTCP. After the silanization, new characteristic peaks were observed.
The band around 1735-1550 cm4 is ascribed to hydroxyl bending after the pro tonation of the TTCP surface, The characteristic of CH2 bending appears around 1490-1380 cm4.
The SUBSTITUTE SHEET (RULE 26) shoulder peak around 1570 cm-1 attributed to NH bending is not observed because of the low content of AEAPS on TTCP surface and overlapping of broad strong hydrogen band around 1650 cm-1. It is also noticed that a special peak at 964 cm-1 exists neither in TTCP nor in AEAPS
spectrum, [00461 The structure P-O-Si resulting from the coupling reaction between the A.EAPS and TTCP may contribute to this newly emerged peak at 964 cm4, The covalent bond was generated between TTCP and AEAPS. 0.5 g TTCP and TTCP-AEAR5 were dispersed into 4 itiL
dichloromethane, respectively. The suspensions were magnetic stirred vigorously for minutes. After that TTCP deposited to the bottom immediately, while the TTCP-AEAPS
solution was even stable after 20 minutes (Fig. 3), Neat TTCP tends to form large agglomerates.
After silanization, most of hydroxyl groups of TTCP have been reacted and AEAPS was covered the TTCP surface, which could increase the stability of the suspension.
[00471 Example 2 [0048] Mechanical property [00491 It is believed that due to the presence of AEAPS on the surface; the interfacial strength was improved. The mechanical strength of PLA/TTCP-AEAPS composites was higher than that of PLA./ TTCP composites with different contents (Figure 4). For example, the tensile strength was 68.4 MPa for PLA/TTCP-AEAPS composite (20 wt% - meaning the overall composite material includes 20wt% modified TTCP-AEAPS). However, it dropped to 515 MPa, when 20 wt% TTCP was incorporated into the matrix. The improved coupling leads to areas with ductile stretched polymer at the interface between PIA and TTCP. The surface modification may contribute to improving the interfacial adhesion. It is well known that there is big agglomeration when inorganic fillers are incorporated into polymeric materials especially at a high loading. Therefore, loosened clusters of TTCP could lead to breakdown of the composite.
[00501 The strength dropped linearly for PLA/TTCP composites. Better interfacial adhesion between filler and polymer matrix may help improve load transfer. The tensile strength was 68.4 MPa even with 20 wt% (meaning the overall composite material includes 20wt% modified TTCP.-.AEAPS) TTCP-AEAPS incorporation, which was 32% increase than that SUBSTITUTE SHEET (RULE 26) of PLA/TTCP composite (20 wt% - meaning the overall composite material includes 20wt?4, non-modified TTCP). In order to fulfill the various requirements, high loading of calcium phosphate cements are required.
[0051] The difference of tensile strength among the composites became smaller at high loading with and without PMDA incorporation. As shown in Figure 3, the tensile modulus increased for all the composites. After incorporating TTCP-AEAPS into the matrix (20 wt% -meaning the overall composite material includes 20wt% modified TTCP-AEAPS), the tensile modulus increased to 2000 MPa from 1550 MPa of pure PLA. It was believed that the functional particle could make contribution to improving the modulus, which might be attributed to good interfacial property. However, no remarkable difference was observed when PMDA
(0.2 wt% -meaning the overall composite material included 0.2wt% PN/TDA) was incorporated into the matrix, It might because there was limited reaction between anhydride and amino group occurred during the compounding process.
[0052] Regarding bending of the materials, TTCP may also contribute to improving the modulus but decreasing the strength (Figure 5), Because of the large agglomeration at high loading, the bending strength dropped even for the PLA/TTCP-AEAPS composites.
The particle would debond easily to enable crack initiation and propagation, Increasing TTCP
fraction increases the agglomeration, and more cracks can form and develop, thus decreasing the strength of the composites. There was no obvious difference among the composites, suggesting that interfacial strength between the particles and matrix was not strong enough, it has been reported that the surface modification method could improve the interfacial adhesion, but these interactions were weak during the bending study. Though the strength of the composites was a little lower compared to that of pure PIA/ the composite could be used in clinic.
[0053] Example 3 [0054] Dynamic mechanical property of PLA/TTCP composites [0055] Figure 6 shows the dynamic storage modulus of PLA and PLA/TTCP
composites (5 wt%) over a temperature range of -50 to 150 C1 It was found that the storage modulus increased with incorporation of filler over the entire temperature range. At -50 'V, the storage SUBSTITUTE SHEET (RULE 26) modulus for PIA was 3.21x109 Pa, which decreased with the increasing temperature; at the glass-transition temperature (Tg = 58.9 C) it dropped significantly. This is attributed to insufficient thermal energy to overcome the potential barrier for transitional and rotational motions of segments of the polymer molecules in the glassy region. Whereas above Tgõ the thermal energy becomes comparable to the potential energy barriers to the segmental motions.
[0056] For PLA/TTCP composite (5 wt% - meaning the overall composite material includes 20wt% modified TTCP-AEAFS), notable enhancement of the storage modulus (32%
increase) was observed in the lower temperature range, indicating that TTCP
had remarkable influence on the elastic properties of the PLA matrix. By incorporating ITCP-AEAPS (5 wt%) into the matrix, the storage modulus was 4.62x109 Pa, which is 44 % higher than that of neat PLA, it is believed that AEAPS was beneficial for the compatibility with the polar polymer matrix (Figure 7A). When 0.2 wt% PMDA (meaning the overall composite material included 0.2wt.% PMDA) was incorporated into the composites, the storage modulus was increased to 4.88x109 Pa (51% increase). The anhydride could react with the amino group which was grafted on the surface of TTCP, thus leading to a better interfacial property (Figure 7B). The anhydride might react with the terminal hydroxyl group of PLA, the interfacial property was improved. These two factors made contribution to the additional increase of the storage modulus. However, the degree of reaction between amino group and anhydride might be low and the increase was not very large. Tg increased from 63.2 C for PLA/TTCP-AEAPS (5% -meaning the overall composite material includes 5wt% modified TTCP-AEAPS) to 65.5 C when PMDA was incorporated into the composite (Figure 6B), signifying that a better interface was generated.
[0057] The foregoing descriptions are not intended to represent the only forms of the compositions and methods according to the present application. The percentages provided herein are by weight unless stated otherwise. Changes in form and in proportion of components, as well as the substitution of equivalents, are contemplated as circumstances may suggest or render expedient. Similarly, while compositions and methods have been described herein in conjunction with specific embodiments, many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description, SUBSTITUTE SHEET (RULE 26)
Claims (26)
1. A method for preparing a polylactide/calcium phosphate containing material comprising the steps of:
combining a calcium phosphate material having a general formula of Ca p(PO4)q X z, where p = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, Cl, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, Cl;
R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl, to form an intermediate silanized calcium phosphate material; and combining polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide, polycaprolactone and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material initiated.
combining a calcium phosphate material having a general formula of Ca p(PO4)q X z, where p = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, Cl, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, Cl;
R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl, to form an intermediate silanized calcium phosphate material; and combining polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide, polycaprolactone and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material initiated.
2. The method of claim 1 wherein the step of combining the calcium phosphate material with a silane material reacts hydroxyl groups on the surface of the calcium phosphate material through alkoxy groups of the silane material to form the intermediate silanized calcium phosphate material.
3. The method of claim 1 wherein the step of combining the calcium phosphate material with the silane material creates a P-O-Si structure in the intermediate silanized calcium phosphate material.
4. The method of claim. 1 wherein the calcium phosphate material surface is protonated.
5. The method of claim 1 wherein combining calcium phosphate material with a silane material includes combining pyromellitic dianhydride with the calcium phosphate material.
6. The method of claim 1 wherein the calcium phosphate material is suspended in an anhydrous solvent.
7. The method of claim 1 wherein the silane material includes N-(2-aminoethyl)-3-aminoproplytrimethoxysilane.
8. The method of claim 1 wherein the intermediate silanized calcium phosphate is filtered and washed with anhydrous solvent for removal of non-bounded coupling agent.
9. A polylactide/calcium phosphate containing material prepared by a process comprising the steps of:
combining a calcium phosphate material having a general formula of Ca p(PO4)q X z, wherepx = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, Cl, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, Cl;
R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl, to form an intermediate silanized calcium phosphate material; and combining a polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide, polycaprolactone and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material.
combining a calcium phosphate material having a general formula of Ca p(PO4)q X z, wherepx = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, Cl, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, Cl;
R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl, to form an intermediate silanized calcium phosphate material; and combining a polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide, polycaprolactone and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material.
10. The polylactide/calcium phosphate containing material of claim 9 wherein combining calcium phosphate material with. the silane material includes combining pyromellitic dianhydride with the calcium phosphate material.
11. The polylactide/calcium phosphate containing material of claim 9 wherein the polylactide/calcium phosphate material has a tensile strength that is at least 1.3 times the tensile strength of a polylactide/calcium phosphate material prepared without combining a silane material.
12. The polylactide/calcium phosphate containing material of claim 10 wherein the polylactide/calcium phosphate material has a tensile strength that is at least 1.3 times the tensile strength of a polylactide/calcium phosphate material prepared without combining a silane material.
13. The polylactide/calcium phosphate containing material of claim 9 wherein combining the calcium phosphate material with the silane material directly reacts with hydroxyl through alkoxy groups of the silane material.
14. The polylactide/calcium phosphate containing material of claim 9 wherein the step of combining the calcium phosphate material with the silane material produces a P-O-Si structure on the surface of the intermediate silanized calcium phosphate material.
15. The polylactide/calcium phosphate containing material of claim 9 wherein the step of combining the calcium phosphate material with the silane material includes combining N-(2-aminoethyl)-3-aminoproplytrimethoxysilane with the calcium phosphate material.
16. The polylactide/calcium phosphate containing material of claim 9 wherein the calcium phosphate material is protonated and suspended in an anhydrous solvent with the silane material includes combining N-(2-aminoethyl)-3-aminoproplytrimethoxysilane.
17. The polylactide/calcium phosphate containing material of claim 9 wherein the anhydrous solvent suspension includes pyromellitic dianhydride.
18. A polylactide/calcium phosphate containing composition comprising:
a calcium phosphate material having a general formula of Ca p(PO4)q X z, where p = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, Cl, Br;
a plurality of P-O-Si structures coupled to the calcium phosphate material;
and lactide containing compounds having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10 coupled to at least a portion of the calcium phosphate material.
a calcium phosphate material having a general formula of Ca p(PO4)q X z, where p = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, Cl, Br;
a plurality of P-O-Si structures coupled to the calcium phosphate material;
and lactide containing compounds having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10 coupled to at least a portion of the calcium phosphate material.
19. A polylactide/calcium phosphate containing composition comprising:
a calcium phosphate material having a general formula of Ca p(PO4)qX2, where where p = 1-10, q = 1-10 and z = 1-5 and X may be OH, O, CO3, F, Cl, Br;
a silane material coupled to the calcium phosphate material, the silane material having an amino group and a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, Cl; R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl;
lactide material polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide and polycaprolactone and mixtures thereof ; and an anhydride coupling the lactide material to the calcium phosphate material via the amino group.
a calcium phosphate material having a general formula of Ca p(PO4)qX2, where where p = 1-10, q = 1-10 and z = 1-5 and X may be OH, O, CO3, F, Cl, Br;
a silane material coupled to the calcium phosphate material, the silane material having an amino group and a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, Cl; R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl;
lactide material polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide and polycaprolactone and mixtures thereof ; and an anhydride coupling the lactide material to the calcium phosphate material via the amino group.
20. The polylactide/calcium. phosphate containing composition of claim 19 wherein the anhydride reacts the terminal hydroxyl group of the lactide and the amino group on the calcium phosphate surface.
21. The polylactide/calcium phosphate containing composition of claim 19 wherein the anhydride is pyromellitic dianhydride.
22. The method of claim 1 wherein the calcium phosphate material is tetracalcium phosphate.
23. The polylactide/calcium. phosphate containing material of claim 9 wherein the calcium phosphate material is tetracalcium phosphate.
24. The polylactide/calcium phosphate containing composition of claim 18 wherein the calcium phosphate material is tetracalcium phosphate.
25. A method for preparing a polylactide/calcium phosphate containing material comprising the steps of:
combining a calcium phosphate material having a general formula of Ca p(PO4)q X z, where p = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, CI, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, CI;
R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl, to form an intermediate silanized calcium phosphate material; and combining polymer selected from the group consisting of a biodegradable polymer selected from the group consisting of polyhydroxybutyrate, poly(hydroxyvalerate, poly(carbonates), polyphosphazene, polyanhydrides, polyurethane, polyesters cellulose, starch, gelatin, chitosan, peptides and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material.
combining a calcium phosphate material having a general formula of Ca p(PO4)q X z, where p = 1-10, q = 1-10 and z = 1-5 and where X may be OH, O, CO3, F, CI, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, CI;
R1, R2, R3 can be the same or different C1-C10 alkyl, R4 is C1-C20 alkyl, to form an intermediate silanized calcium phosphate material; and combining polymer selected from the group consisting of a biodegradable polymer selected from the group consisting of polyhydroxybutyrate, poly(hydroxyvalerate, poly(carbonates), polyphosphazene, polyanhydrides, polyurethane, polyesters cellulose, starch, gelatin, chitosan, peptides and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material.
26. A method for preparing a polylactide/calcium phosphate containing material comprising the steps of:
combining a calcium phosphate material selected from the group consisting of hydroxyapatite, tricalcium phosphate, tetracalcium phosphate, monocalcium phosphate, dicalcium phosphate, amorphous calcium phosphate, octacalcium phosphate substitued with X
where X may be OH, O, CO3, F, CI, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, CI; R1, R2, R3 can be the same or different from alkyl (C1-C10), R4 is alkyl (C1-C20), to form an intermediate silanized calcium phosphate material; and combining polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide, polycaprolactone and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material initiated.
combining a calcium phosphate material selected from the group consisting of hydroxyapatite, tricalcium phosphate, tetracalcium phosphate, monocalcium phosphate, dicalcium phosphate, amorphous calcium phosphate, octacalcium phosphate substitued with X
where X may be OH, O, CO3, F, CI, Br with a silane material having a general formula of (R1O)(R2O)(R3O)Si-R4-Y, where Y can be OH, NH2, SH, CI; R1, R2, R3 can be the same or different from alkyl (C1-C10), R4 is alkyl (C1-C20), to form an intermediate silanized calcium phosphate material; and combining polymer selected from the group consisting of a lactide material having a general formula of -(OCR1R2CO)n- or -(R3COO)n-, where R1, R2, R3 can be any of H, alkyl less than C10, polyglycolide, polylactide-co-glycolide, polycaprolactone and mixtures thereof with the intermediate silanized calcium phosphate material to form the polylactide/calcium phosphate material initiated.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261623490P | 2012-04-12 | 2012-04-12 | |
| US201261623483P | 2012-04-12 | 2012-04-12 | |
| US61/623,483 | 2012-04-12 | ||
| US61/623,490 | 2012-04-12 | ||
| PCT/US2013/029858 WO2013154705A1 (en) | 2012-04-12 | 2013-03-08 | Polylactide and calcium phosphate compositions and methods of making the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2870188A1 true CA2870188A1 (en) | 2013-10-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA2870188A Abandoned CA2870188A1 (en) | 2012-04-12 | 2013-03-08 | Polylactide and calcium phosphate compositions and methods of making the same |
Country Status (4)
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| US (3) | US10400083B2 (en) |
| EP (1) | EP2836546B1 (en) |
| CA (1) | CA2870188A1 (en) |
| WO (2) | WO2013154705A1 (en) |
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| CN106963978B (en) * | 2017-05-17 | 2020-01-31 | 南宁越洋科技有限公司 | Preparation method of artificial tooth with PLLA/nHA surface active coating and imitating artificial bone material |
| CN112662152B (en) * | 2020-12-23 | 2022-07-05 | 山西生物质新材料产业研究院有限公司 | Polylactic acid-based degradable composite material, preparation method and application of polylactic acid-based degradable composite material as mulching film |
| CN116832223B (en) * | 2023-07-27 | 2024-01-30 | 重庆生物智能制造研究院 | Medical absorbable calcium phosphate salt/polyester composite material and preparation method thereof |
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2013
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- 2013-03-08 US US14/391,044 patent/US10400083B2/en active Active
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- 2013-03-08 WO PCT/US2013/029858 patent/WO2013154705A1/en active Application Filing
- 2013-03-08 CA CA2870188A patent/CA2870188A1/en not_active Abandoned
- 2013-03-08 WO PCT/US2013/029839 patent/WO2013154704A1/en active Application Filing
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2019
- 2019-07-24 US US16/520,762 patent/US11267950B2/en active Active
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| EP2836546A1 (en) | 2015-02-18 |
| US11267950B2 (en) | 2022-03-08 |
| US9399708B2 (en) | 2016-07-26 |
| WO2013154704A1 (en) | 2013-10-17 |
| US10400083B2 (en) | 2019-09-03 |
| US20150065739A1 (en) | 2015-03-05 |
| US20150065632A1 (en) | 2015-03-05 |
| EP2836546A4 (en) | 2015-11-11 |
| EP2836546B1 (en) | 2020-02-19 |
| WO2013154705A1 (en) | 2013-10-17 |
| US20200190281A1 (en) | 2020-06-18 |
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